Neurons in the retina make remarkably precise connections with their synaptic targets. Indeed, such precision is a hallmark of neuronal connectivity in many parts of the brain. These connections define the wiring diagram of the nervous system, and are critical to how the brain computes. Many of these connections are genetically programmed, forming in exactly the same pattern independent of visual experience, or the activity of the developing brain. However, the molecular mechanisms by which the genome encodes information about these connections, and the cell biological mechanisms by which these connections form during development are poorly understood. The visual system of Drosophila provides a unique context in which to use genetic, molecular genetic and histological techniques to define these mechanisms. The proposed experiments examine these mechanisms in the context of how specific cell adhesion and cell signaling molecules can guide axons to specific targets. How can precise connections be genetically hard-wired at the level of single cells and their processes? (Aim 1) How are differences in the relative levels of cell adhesion molecules translated into directed changes in axonal trajectory. (Aim 2). How do cell signaling pathways specify which part of the visual system should be innervated? (Aim 3). How does the genetic machinery coordinate the choice of post-synaptic partner with the functional architecture of the retina? These experiments will define critical molecular mechanisms that underlie neural architecture. As mutations in the human homologs of the proteins studied here are associated with inherited forms of macular dystrophy and retinitis pigmentosa, understanding the normal functions of these molecules in mechanistic detail will inform novel therapeutic strategies in the treatment of eye disease. PUBLIC HEALTH RELEVANCE: Mutations in a number of cellular proteins cause retinitis pigmentosa, retinal dystrophy and macular degeneration, causing impaired vision and blindness. This study will examine the functions of several of these proteins during eye development, will inform our broad understanding of how these proteins normally act, and will benefit the creation of new treatment strategies.